What heart rate controller, such as beta-blockers (e.g. esmolol), can be used in patients with sepsis to reduce tachycardia and improve cardiac output?

Heart Rate Control in Sepsis

Primary Recommendation

Selective beta-1 antagonists, specifically esmolol or landiolol, can be used for heart rate control in septic patients with persistent tachycardia after initial hemodynamic stabilization, but this approach requires careful patient selection and continuous monitoring to avoid hemodynamic compromise. 1

Rationale for Beta-Blocker Use in Sepsis

The physiologic basis for heart rate control in sepsis stems from evidence that excessive sympathetic stimulation becomes pathological rather than adaptive 1:

• High circulating catecholamines and persistent tachycardia are associated with increased mortality in septic shock 1
• Short-acting β1 antagonists may provide cardiovascular benefits by slowing heart rate, improving diastolic filling time, enhancing coronary perfusion, and optimizing myocardial oxygen consumption 1

Agent Selection

Esmolol (First-Line Beta-Blocker for Sepsis)

Esmolol is the preferred agent due to its cardioselective β1 receptor antagonism, rapid onset (5 minutes), and ultra-short duration of action, allowing for rapid titration and immediate reversal if adverse effects occur 1, 2:

• Loading dose: 500 mcg/kg IV over 1 minute (optional) 2
• Maintenance infusion: Start at 50 mcg/kg/min, titrate up to 200 mcg/kg/min based on heart rate response 2
• Target heart rate: 80-94 beats per minute in most sepsis studies 3

Landiolol (Alternative Agent)

Landiolol is an ultra-short acting β-blocker approximately eight times more selective for the β1 receptor than esmolol, though availability is limited in many countries 1

Clinical Evidence and Outcomes

Mortality Benefit (Strongest Evidence)

The landmark 2013 randomized trial by Morelli et al. demonstrated striking mortality reduction 3:

• 28-day mortality: 49.4% in esmolol group vs 80.5% in control group (adjusted HR 0.39; 95% CI 0.26-0.59; P<0.001) 3
• Target heart rate (80-94 bpm) was achieved in 100% of esmolol patients vs minimal reduction in controls 3
• Stroke volume index and left ventricular stroke work index improved despite heart rate reduction 3
• Norepinephrine requirements decreased significantly (median AUC -0.11 vs -0.01 μg/kg/min, P=0.003) 3
• Arterial lactate levels improved (median AUC -0.1 vs 0.1 mmol/L, P=0.007) 3

Hemodynamic Effects

Esmolol reduces heart rate while maintaining or improving stroke volume through enhanced diastolic filling, resulting in preserved or slightly reduced cardiac output 4, 3:

• Microcirculatory blood flow in small vessels improved (2.8 to 3.0, P=0.002) with reduced heterogeneity index 4
• Norepinephrine requirements decreased by approximately 23% despite heart rate reduction 4
• Tissue perfusion markers (lactate, ScvO2) remained stable or improved 4, 3

Combination Therapy

Milrinone combined with esmolol showed synergistic benefits in severe sepsis, with milrinone's positive inotropy offsetting esmolol's negative chronotropy 5:

• Heart rate control success: 60% with milrinone-esmolol vs 33.3% with milrinone alone vs 26.7% with standard care 5
• 28-day survival improved significantly with combination therapy 5

Critical Patient Selection Criteria

Appropriate Candidates

Beta-blockers should only be considered in septic patients who meet ALL of the following criteria 1, 3:

• Persistent tachycardia (HR ≥95 bpm) after at least 24 hours of hemodynamic optimization and initial resuscitation 3
• Hyperkinetic circulation (elevated cardiac index, typically >4 L/min/m²) 6, 7
• Adequate fluid resuscitation completed (minimum 30 mL/kg crystalloid) 8
• Mean arterial pressure ≥65 mmHg maintained with vasopressors 8, 3
• No evidence of decompensated heart failure or cardiogenic shock 2
• Absence of severe bradycardia, heart block >first degree, or sick sinus syndrome 2

Absolute Contraindications

Do not use esmolol in septic patients with 2:

• Severe sinus bradycardia or heart block greater than first degree 2
• Decompensated heart failure or cardiogenic shock 2
• Cardiodepressant calcium-channel antagonist use (e.g., verapamil) in close temporal proximity 2
• Pulmonary hypertension 2
• Known hypersensitivity to esmolol 2

Practical Implementation Algorithm

Step 1: Initial Assessment (Before Esmolol)

Confirm the patient has completed initial resuscitation and remains hemodynamically stable 8, 3:

• Minimum 30 mL/kg crystalloid administered 8
• MAP ≥65 mmHg on stable vasopressor doses 8
• Cardiac index >3.5-4.0 L/min/m² (hyperkinetic state) 6, 7
• Persistent HR >95 bpm for >24 hours after stabilization 3

Step 2: Initiate Esmolol Infusion

Start with conservative dosing and titrate slowly 2, 3:

• Optional loading dose: 500 mcg/kg over 1 minute 2
• Initial maintenance: 50 mcg/kg/min 2
• Titrate upward by 25-50 mcg/kg/min every 4 minutes based on heart rate and hemodynamic response 2
• Target heart rate: 80-94 bpm (approximately 20% reduction from baseline) 3
• Maximum dose: 200 mcg/kg/min 2

Step 3: Continuous Monitoring Requirements

Mandatory monitoring during esmolol infusion 8, 2:

• Continuous arterial blood pressure via arterial catheter 8
• Continuous cardiac rhythm monitoring 2
• Cardiac output/cardiac index measurement (preferably continuous) 4, 3
• Hourly assessment of tissue perfusion: lactate, ScvO2, urine output, mental status, capillary refill 8
• Vasopressor requirements (expect potential increase initially) 4, 6

Step 4: Dose Adjustment Based on Response

Titrate esmolol based on hemodynamic tolerance 6, 3:

• If MAP drops <65 mmHg: Reduce esmolol dose by 50% and increase norepinephrine 6
• If norepinephrine requirement increases >50%: Consider reducing or stopping esmolol 6
• If cardiac index drops below 2.5 L/min/m² with signs of hypoperfusion: Stop esmolol immediately 6
• If target HR achieved with stable hemodynamics: Maintain current dose 3

Critical Warnings and Pitfalls

Timing Considerations

Very early esmolol administration (within 6-12 hours of shock onset) carries significantly higher risk 6:

• In one study, 3 of 9 patients required early esmolol cessation due to marked norepinephrine increases and persistent cardiac failure 6
• Cardiac index decreased from 4.2 to 2.9 L/min/m², with worsening of systolic, diastolic, and biventricular function parameters 6
• The 24-hour stabilization period used in successful trials appears critical for safety 3

Hypotension Risk

Symptomatic hypotension occurs in approximately 12% of patients receiving esmolol, with asymptomatic hypotension in up to 50% 2:

• Hypotension is rapidly reversible with dose reduction or discontinuation 2
• Increased vasopressor requirements should be anticipated and are not necessarily an indication to stop esmolol if tissue perfusion remains adequate 4, 3

Bradycardia and Cardiac Failure

Monitor closely for excessive bradycardia, heart block, and cardiac decompensation 2:

• At first sign of impending cardiac failure, stop esmolol immediately and initiate supportive therapy 2
• Severe bradycardia, sinus pause, heart block, and cardiac arrest have been reported 2

Reactive Airways Disease

Use extreme caution in patients with bronchospastic disease 2:

• Despite β1 selectivity, bronchospasm can occur 2
• If bronchospasm develops, stop infusion immediately and consider β2 agonist therapy 2

Metabolic Considerations

Beta-blockers mask hypoglycemic tachycardia in diabetic patients, though other manifestations (dizziness, sweating) remain 2:

• Monitor glucose closely in diabetic patients 2
• Esmolol may enhance hypoglycemic effects of antidiabetic agents 2

Infusion Site Reactions

Avoid small veins and butterfly catheters due to risk of thrombophlebitis, necrosis, and blistering with extravasation 2:

• Use central venous access when possible 8
• If local reaction develops, change infusion site immediately 2

Contraindication in Specific Sepsis Contexts

Hypovolemic Patients

Esmolol attenuates reflex tachycardia and increases hypotension risk in inadequately resuscitated patients 2:

• Ensure complete fluid resuscitation before initiating beta-blockade 8, 3

Pheochromocytoma

If pheochromocytoma is suspected, beta-blockers must only be given AFTER alpha-blockade is established 2:

• Beta-blockade alone causes paradoxical hypertension from unopposed alpha-mediated vasoconstriction 2

Peripheral Vascular Disease

Esmolol may worsen peripheral circulatory disorders including Raynaud's phenomenon and peripheral occlusive vascular disease 2

Discontinuation Protocol

Abrupt discontinuation should be avoided in patients with coronary artery disease 2:

• Severe exacerbations of angina, myocardial infarction, and ventricular arrhythmias have been reported with abrupt beta-blocker cessation 2
• Heart rate increases moderately above pre-treatment levels within 30 minutes of esmolol discontinuation due to its ultra-short half-life 2
• Observe patients for signs of myocardial ischemia when discontinuing therapy 2

Current Guideline Position

Despite promising research data, beta-blockers for heart rate control in sepsis are NOT currently recommended in major sepsis guidelines 1:

• The 2018 Intensive Care Medicine perspective acknowledges the potential benefits but notes this remains an investigational approach 1
• The evidence base, while compelling, consists primarily of single-center studies and requires validation in multicenter trials 3
• This therapy should be considered experimental and used only in highly selected patients with appropriate monitoring capabilities 1

Comparison to Standard Rate Control Agents

Esmolol differs fundamentally from agents used for atrial fibrillation rate control 1:

• In atrial fibrillation, esmolol is Class I recommended for rate control in high adrenergic states (e.g., postoperative) 1
• However, sepsis represents a different pathophysiologic context where tachycardia may be compensatory 1
• The sepsis application requires distinguishing pathologic from compensatory tachycardia, which remains clinically challenging 6